本文關(guān)鍵詞： 小耳畸形 伴發(fā)畸形 遺傳特征 候選基因　出處：《北京協(xié)和醫(yī)學院》2017年博士論文　論文類型：學位論文

【摘要】：目的先天性小耳畸形是體表重大畸形,嚴重影響患者的外貌和心理健康,進行小耳畸形發(fā)病特征和相關(guān)遺傳學研究意義重大。本研究探討中國小耳畸形患者伴發(fā)畸形的發(fā)生情況和特點,分析之間的關(guān)聯(lián);經(jīng)過對家族史的詳細調(diào)查,了解小耳畸形患者的遺傳特征;在小耳畸形患者中進行候選基因序列變異和拷貝數(shù)變異檢測,對變異進行生物信息學分析。通過以上研究逐步深化對小耳畸形的認知,可作為今后小耳畸形分子機制的研究和防治的基礎(chǔ)。方法1.在基于醫(yī)院的研究中選取2014年12月-2016年2月間小耳畸形患者,對所有非綜合征型小耳畸形患者672例進行詳細地體格檢查,并記錄相關(guān)伴發(fā)畸形。將伴發(fā)畸形根據(jù)受影響的主要器官系統(tǒng)進行分類,采用SPSS 19.0統(tǒng)計學軟件分析小耳畸形與伴發(fā)畸形間的關(guān)系。并與其他國家地區(qū)的小耳伴發(fā)畸形資料對比分析中國小耳群體患病特點。2.對上述672個患者通過查體、直接詢問及電話隨訪的方法獲得患者的家系資料及耳部畸形發(fā)病情況并登記。主要調(diào)查對象為先證者、一級親屬、二級親屬、三級親屬、四級親屬,按照小耳畸形患者是否具有耳部畸形家族史背景分為家族史組和散發(fā)組,對數(shù)據(jù)進行統(tǒng)計學分析,探尋有價值的規(guī)律。3.隨機選取200例散發(fā)小耳畸形患者對六個候選基因(HOXA1、HOXA2、EYA1、SIX1、SALL1、FGF3)進行序列變異和拷貝數(shù)變異檢測,并利用生物信息學分析變異的危害。結(jié)果1.本研究顯示了男性(72%)、單側(cè)(92.99%)和右側(cè)(63%)多發(fā),與文獻中的結(jié)果一致。我們在293(43.6%)位患者中發(fā)現(xiàn)了一項及以上的伴發(fā)畸形,尤其是耳面頸系統(tǒng)、肌肉骨骼系統(tǒng)、心血管系統(tǒng)伴發(fā)率最高。耳廓發(fā)育程度越差伴發(fā)畸形率越高。小耳不同伴發(fā)畸形比例有顯著異質(zhì)性,但大體在器官系統(tǒng)畸形方面的權(quán)重是相符的,即伴發(fā)畸形最常累及的是耳面頸系統(tǒng),接下來是肌肉骨骼系統(tǒng),然后是心血管系統(tǒng),后面是泌尿生殖系統(tǒng),呼吸系統(tǒng)、神經(jīng)系統(tǒng)、消化系統(tǒng)等較少累及。2.本研究中耳部畸形家族史陽性率為34.1%,其中一級親屬所占比例最高,二、三、四級親屬比例依次減少,符合遺傳學規(guī)律,且父母兩系背景在各級小耳畸形患者人數(shù)構(gòu)成比無統(tǒng)計學差異。有33.8%小耳畸形患者伴發(fā)附耳/瘺管,且這部分患者比單純小耳患者有更高的家族耳部畸形發(fā)生率。3.在200例患者中,鑒定出1例患者HOXA2基因的錯義突變(c.260CT,p.A87V),此突變不存在于患者父母,為新發(fā)突變,在1000 human genome、HGMD、ESP6500、dbSNP和ExAC等數(shù)據(jù)庫中未查到相關(guān)記錄,經(jīng)生物信息學分析該突變高度保守,推測其具有致病性。檢測到兩例患者存在EYA1基因的拷貝數(shù)缺失,推測為小耳畸形的致病原因。結(jié)論1.本研究是中國小耳患者中第一份有關(guān)伴發(fā)畸形的詳細專題性研究,小耳患者的伴發(fā)畸形率較高,且臨床異質(zhì)性較大,為了探索小耳畸形病因及為患者提供更好的治療,應(yīng)加大未來對相關(guān)伴發(fā)畸形的研究力度。2.本研究結(jié)合其他耳部畸形多發(fā)性,將家屬耳部畸形納入研究并證實耳部畸形家族史發(fā)生率為34.1%,且存在垂直傳遞、隔代遺傳和家族聚集的遺傳特征。在研究小耳畸形遺傳特征時不應(yīng)忽略親屬中的其他耳畸形。雖然小耳畸形目前發(fā)病機制不明,但遺傳因素不容忽視。3.本研究分別對200例散發(fā)小耳患者六個候選基因進行了序列變異和拷貝數(shù)變異檢測,成功地鑒定了一例患者存在HOXA2基因編碼區(qū)的c.260CT(p.A87V)突變,此突變位于exon1,為國際首次報道,擴增了小耳畸形HOXA2基因突變譜;并且在兩例患者中檢測到EYA1基因拷貝數(shù)缺失。這些發(fā)現(xiàn)可能是小耳畸形的致病因素,其發(fā)病機制,有待下一步研究驗證。
[Abstract]:The purpose of congenital microtia is a major body deformity, seriously affect the patient's appearance and mental health, study significance of microtia disease characteristics and related genetics. Major of this study was to investigate the occurrence and characteristics of deformity with Chinese microtia patients, correlation analysis between; after a detailed investigation of family history, understand the genetic characteristics of patients with microtia; and the copy number variation of candidate gene sequence variation detection in patients with microtia, bioinformatics analysis of variation. Through the above study, the gradual deepening of the microtia cognition, can be used as a basis for future research and the prevention of microtia molecular mechanism. Methods 1. in December 2014 select the -2016 in February of microtia patients in hospital in the study based on the physical examination of 672 cases with all non syndromic patients with microtia, and record The associated malformation accompanied malformations. According to the main organ system affected the classification, using SPSS 19 statistical software to analyze the relationship between microtia and associated malformations. With comparative analysis of the data Chinese small ear malformation group prevalence characteristics of.2. of the 672 patients through the examination with other countries and regions of the small ear method, direct examination and telephone follow-up for patients with family data and ear deformity incidence and registration. The main research object for the proband, first-degree relatives, two relatives, three relatives, four relatives, according to the patients with microtia is not with ear deformity family history background into family history group and the sporadic group, the statistical analysis of the data, to explore the value of.3. in 200 randomly selected patients with sporadic microtia in six candidate genes (HOXA1, HOXA2, EYA1, SIX1, SALL1, FGF3) sequence variation and copy number variation Abnormal detection, and the use of bioinformatics analysis of variation of harm. 1. results of this study shows that male (72%), unilateral (92.99%) and right (63%) multiple, consistent with the results in the literature. We in 293 (43.6%) patients were found in one or more of the associated anomalies, especially the ear is the face and neck system, musculoskeletal system, cardiovascular system and the incidence rate of the highest degree of development. The worse ear malformations was higher. Small ear malformations have significantly different proportion of heterogeneity, but generally in the organ system abnormalities weight is consistent, which is associated with the most frequently involved is deformity next is the ear of face and neck system, musculoskeletal system, and then is behind the cardiovascular system, genitourinary system, respiratory system, nervous system, digestive system and the positive rate of less involved.2. this study of middle ear malformation family history was 34.1%, of which the first-degree relatives of the highest proportion, two, three, four In order to reduce the proportion of relatives, comply with the laws of genetics, and the parental background at all levels of two-line microtia patients who showed no significant difference. There are 33.8% patients with fistula / ear hair with microtia, and these patients than microtia patients had a higher incidence of.3. family ear deformity in 200 patients, 1 patients identified missense mutations in the HOXA2 gene (c.260CT, p.A87V), this mutation does not exist in patients with parents, is a new mutation in 1000 human, genome, HGMD, ESP6500, dbSNP and ExAC in the database did not find relevant records, by bioinformatics analysis of the mutations are highly conserved, presumably with pathogenicity. Two patients have detected EYA1 gene copy number is missing, presumed cause of microtia. Conclusion: 1. this study is Chinese with the first small ear malformations with the special study, patients with small ears The malformation rate is higher, and the heterogeneity is larger, in order to explore the microtia etiology and provide better treatment for patients, should increase the future of related research efforts with.2. deformity combined with the other ear deformity of multiple family members, will be included in the study and confirmed that the ear ear deformity deformity of the family history of incidence was 34.1%. And there are vertical transmission, genetic characteristics of atavism and family aggregation. In the study of genetic characteristics of microtia should not ignore other relatives in ear microtia malformation. Although the pathogenesis is unknown, but genetic factors can not be ignored in this study were.3. in 200 cases of sporadic microtia and six candidate genes were and copy number variation detection of sequence variation, successfully identified HOXA2 gene encoding region in a patient with c.260CT (p.A87V) mutation, the mutation in exon1, reported for the first time international, the amplification of microtia H OXA2 gene mutation spectrum and EYA1 gene copy number deletion were detected in two patients. These findings may be the pathogenic factors of microtia, and its pathogenesis needs further research and verification.

【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R764.7

【相似文獻】

相關(guān)期刊論文 前10條

1 吳燕里 ,汪英 ,張寧寧;皮膚軟組織擴張術(shù)治療小耳畸形的護理[J];中華整形外科雜志;2002年S1期

2 吳燕里,張寧寧,汪英;皮膚軟組織擴張術(shù)治療小耳畸形病人的護理[J];護理學雜志;2003年02期

3 石鐵鋼,羅t，

本文編號：1554787